Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody Journal Article


Authors: Iwama, S.; De Remigis, A.; Callahan, M. K.; Slovin, S. F.; Wolchok, J. D.; Caturegli, P.
Article Title: Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody
Abstract: Hypophysitis is a chronic inflammation of the pituitary gland of unknown (primary forms) or recognizable (secondary forms) etiology, such as the use of ipilimumab in cancer immunotherapy. Ipilimumab, which blocks the T cell inhibitory molecule CTLA-4 (cytotoxic T lymphocyte antigen-4), induces hypophysitis in about 4% of patients through unknown mechanisms. We first established a model of secondary hypophysitis by repeated injections of a CTLA-4 blocking antibody into SJL/J or C57BL/6J mice, and showed that they developed lymphocytic infiltration of the pituitary gland and circulating pituitary antibodies. We next assessed the prevalence of pituitary antibodies in a cohort of 20 patients with advanced melanoma or prostate cancer, 7 with a clinical diagnosis of hypophysitis, before and after ipilimumab administration. Pituitary antibodies, negative at baseline, developed in the 7 patients with hypophysitis but not in the 13 without it; these antibodies predominantly recognized thyrotropin-, follicle-stimulating hormone-, and corticotropin-secreting cells. We then hypothesized that the injected CTLA-4 antibody could cause pituitary toxicity if bound to CTLA-4 antigen expressed "ectopically" on pituitary endocrine cells. Pituitary glands indeed expressed CTLA-4 at both RNA and protein levels, particularly in a subset of prolactin- and thyrotropin-secreting cells. Notably, these cells became the site of complement activation, featuring deposition of C3d and C4d components and an inflammatory cascade akin to that seen in type II hypersensitivity. In summary, the study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab, and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis.
Keywords: adult; clinical article; controlled study; aged; middle aged; unclassified drug; advanced cancer; nonhuman; neurotoxicity; antigen expression; mouse; animal tissue; cytotoxic t lymphocyte antigen 4 antibody; ipilimumab; melanoma; animal experiment; animal model; prostate cancer; disease model; lymphocytic infiltration; cytotoxic t lymphocyte antigen 4; autoantibody; antibody production; thyrotropin; follitropin; prolactin; corticotropin; hypophysitis; hypersensitivity; antibody blood level; complement activation; human; male; female; priority journal; article; complement component c3d; complement component c4d; pituitary autoantibody; acth secreting cell; tsh secreting cell
Journal Title: Science Translational Medicine
Volume: 6
Issue: 230
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2014-04-02
Start Page: 230ra45
Language: English
DOI: 10.1126/scitranslmed.3008002
PROVIDER: scopus
PUBMED: 24695685
DOI/URL:
Notes: Sci. Transl. Med. -- Cited By (since 1996):1 -- Export Date: 2 June 2014 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Susan Slovin
    186 Slovin
  2. Jedd D Wolchok
    669 Wolchok
  3. Margaret Kathleen Callahan
    103 Callahan